Process for preparing heteroarylbenzoxepin-acetic acids, precursors and derivatives thereof

ABSTRACT

Heteroarylbenzoxepin-acetic acids, esters thereof, novel precursors thereof, pharmaceutically acceptable salts thereof and processes for their preparation are disclosed. These compounds are useful as antiinflammatory and analgesic agents.

This is a division, of application Ser. No. 607,926, filed Aug. 26,1975, now U.S. Pat. No. 4,025,640.

This invention relates to heteroarylbenzoxepin-acetic acids, esters andprecursors thereof and pharmaceutically acceptable salts thereof havingartiinflammatory and analgesic activity.

To the best of our knowledge, the compounds of the present inventionhave not heretofore been described. Sulfur compounds of the formula:##STR1## and derivatives thereof are mentioned as having analgesic,antipyretic and antiinflammatory activity in Japanese Patent PublicationNo. 72 00 425, published Jan. 7, 1972. U.S. patent application ofHelsley et al., Ser. No. 459,774, filed Apr. 10, 1974, teaches6,11-dihydrodibenz[b,e]oxepin-acetic acids and derivatives thereofdemonstrating antiinflammatory and analgesic activity. The tricycliccompounds of the present invention have significant structuraldifferences and display unanticipated good activity.

The compounds of the invention have the formulae ##STR2## wherein X,together with the carbon atoms to which it is attached, is a 5 or6-membered heteroaryl ring structure containing from 1 to 2 oxygen,nitrogen or sulfur atoms; R is hydrogen or straight or branched chainalkyl of from 1 to 5 carbon atoms; R¹ is hydrogen or lower alkyl of 1 to4 carbon atoms; R² is hydrogen or methyl; and n is the integer 1, 2 or3; and pharmaceutically acceptable salts thereof prepared from suitablebases. Contemplaed as separate embodiments of the invention are thedicarboxylic acids and tricyclic compounds. Also contemplated to beseparate embodiments are the carboxylic acids (R is hydrogen) and estersthereof (R is alkyl). Preferred compounds are those wherein theheteroaryl ring is unsubstituted. More preferred compounds are thosewherein the heteroaryl ring is furan or thiophene.

The compounds of the present invention are prepared by one of themethods below.

METHOD A

1. A lower alkyl ester, an ester with 1 to 4 carbon atoms in thealcoholic unit, of the formula ##STR3## wherein X together with thecarbon atoms to which it attaches, R¹ and n are as defined earlier and Yis halogen, is allowed to react with a lower alkyl ester of a(hydroxyphenyl)acetic acid in the presence of a solvent such as acetone,butanone, ethanol or dimethylformamide, an acid scavenger such aspotassium carbonate or sodium ethoxide and with or without a reactioninitiator such as potassium or sodium iodide at a temperature of fromambient to the boiling point of the solvent for from a few minutes to 72hours to provide a corresponding diester of the formula ##STR4##

2. Saponifying the diester to its corresponding dicarboxylic acid by asuitable method known to the art. A preferred method utilizes a basesuch as sodium or potassium hydroxide in a solvent such as aqueousethanol or water for a time of from 15 minutes to 24 hours and at atemperature of from ambient to the boiling point of the solvent.

3. The dicarboxylic acid is cyclized by treatment with a dehydratingagent such as polyphosphoric acid, ethanol-phosphorus pentoxide orsulfuric acid, with or without a solvent such as tetramethylenesulfoneor acetic acid, at a temperature of from 50° to 125° C. and for a timeof from 5 minutes to 12 hours to provide a heteroarylbenzoxepin-aceticacid, a compound of the invention of the formula ##STR5##

METHOD B

1. A diacid halide is prepared by the treatment of a dicarboxylic acid,prepared above in Method A, step 2, with a sufficient amount of an agentsuch as thionyl halide or phosphorus pentahalide in the presence orabsence of a solvent, at a temperature of from ambient to the refluxpoint of the reaction mixture, and for from 15 minutes to 6 hours.

2. The diacid halide is cyclized under Friedel-Carfts conditions andthen hydrolyzed by a method known to the art to provide a compound ofthe invention as defined in Method A, step 3. A preferred method ofcyclization utilizes a Lewis acid such as stannic chloride at ambienttemperature. Alternatively the diacid halide can be subjected to thermalcyclization by heating to a temperature of from 80° to 125° C. for from10 minutes to 24 hours and then hydrolyzed to produce a compound of theinvention.

METHOD C

A compound of the invention, prepared by either Method A or B, isesterified by allowing it to react with an alcohol of the formula ROH;wherein R is as defined earlier, in the presence of an acid such assulfuric, hydrochloric or p-toluenesulfonic, at a temperature of from50° C. to the boiling point of the alcohol, and for from 15 minutes to24 hours.

As well known to those skilled in the art, reaction times are correlatedto the reaction temperatures in the sense that shorter times are neededwhen using higher temperature.

The tricyclic compounds of the present invention are useful as systemicantiinflammatory agents due to their ability to suppress inflammation inmammals. The activity of the compounds is demonstrated in thecarrageenin induced rat paw edema antiinflammatory assay [Proc. Soc.Exptl. Biol. Med., III, 544 (1962); J. Pharmacol. Exp. Ther., 141, 369(1963)]. For example, at oral doses of 3.6, 4.2 and 24 mg/kg of bodyweight, respectively,4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid, methyl4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate and4,10-dihydro-10-oxofurano[3,2-c][1]benzoxepin-8-acetic acid, exhibit anapproximately 50% of edema.

The tricyclic compounds of the present invention are also useful astopical antiinflammatory agents due to their ability to suppress dermalinflammation in mammals. The activity of representative compounds isdemonstrated in the croton oil induced edema assay in mice[Endocrinology, 77, 625 (1965); Clin, Pharmacol. and Therap., 16, 900(1974)]. For example, when applied topically at concentrations of 2.5%and 5% respectively,4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid and methyl4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate exhibit,respectively, a 65 and 24%inhibition of edema.

The tricyclic compounds of the present invention are also useful asanalgesic agents due to their ability to alleviate pain in mammals.Representative compounds of the invention demonstrate this activity inthe 2-phenyl-1,4-benzoquinone-induced writhing test in mice, a standardassay for analgesia [Proc. Soc. Expt]. Biol. Med., 95, 729 (1957)]. Forexample, at oral doses of 4.5 and 45.0 mg/kg of body weight,4,10-dihydro-10-oxothieno-[3,2-c][1]benzoxepin-8-acetic acid and4,10-dihydro-10-oxothieno-[3,2-c][1]benzoxepin-8-acetic acid and4,10-dihydro-10-oxofurano-[3,2-c][1]benzoxepin-8-acetic acid,respectively, exhibit an approximately 50% inhibition of edema.

These data illustrate that the compounds of this invention are useful assystemic antiinflammatory and/or analgesic agents at a dose of from 0.1to 50 mg/kg of body weight and as topical antiinflammatory agents atconcentrations of from 0.1 to 20%.

Examples of compounds of the invention include:

4,10-dihydro-10-oxothieno[3,4-c][1]benzoxepin-7-acetic acid;

Ethyl 4,10-dihydro-10-oxofurano[3,2-c][1]benzoxepin-8-acetate;

Amyl4,10-dihydro-1,2,3-trimethyl-10-oxopyrrolo-[3,4-c][1]benzoxepin-8-aceticacid;

5,11-dihydro-11-oxopyrazino[2,3-c][1]benzoxepin-8-acetic acid;

5,11-dihydro-11-oxopyrimido[4,5-c][1]benzoxepin-9-acetic acid;

n-Propyl 4,10-dihydro-10-oxooxazolo[4,5-c][1]benzoxepin-8-acetate;

4,10-dihydro-10-oxothiazolo[4,5-c][1]benzoxepin-8-acetic acid;

n-Butyl 4,10-dihydro-10-oxoimidazo[4,5-c][1]benzoxepin-7-acetate;

4,10-dihydro-10-oxothieno[2,3-c][1]benzoxepin-8-acetic acid;

4,10-dihydro-N-methyl-10-oxothieno[3,2-c][1]benzoxepin-S-acetic acid;

4,10-dihydro-N-methyl-10-oxofurano[2,3-c][1]benzoxepin-7-acetic acid;and

4,10-dihydro-10-oxoisoxazolo[4,5-c][1]benzoxepin-8-acetic acid.

Effective quantities of the tricyclic compounds of the invention may beadministered to a patient by any one of various methods, for example,orally as in capsules or tablets, topically as in ointments, solutionsor salves, parenterally in the form of sterile solutions or suspensions,and in some cases intraveneously in the form of sterile solutions. Thefree acid final products, while effective themselves, may be formulatedand administered in the form of their pharmaceutically acceptableaddition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like. Such salts includethose of sodium, potassium, calcium, magnesium or ammonium.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-500 milligrams of active compound.

The tablets, pills, capsules, irocies, and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit forexample, as coatings. Thus, tablets or pills may be coated with sugar,Shellac, or other enterie coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent, andcertain preservatives, dyes and colorings, and flavors. Materials usedin preparing these various compositions should be pharmaceutically pureand non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied to be between 0.5 and about 30% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfite;chelati agents such as ethylenediaminetetraacetic acid; buffers such asacetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenter preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

For the purpose of topical administration, the active compounds of theinvention may be incorporated into a solution, suspension, ointment,cream or salve. These preparations should contain at least 0.01% ofactive compound but may be varied to be between 0.05 and about 20% ofthe weight thereof. The amount of active compound is such compositionsis such that a suitable dosage will be obtained. Preferred topicallyadministre preparations should contain between 0.1 and 10% of activecompounds.

The topical compositions may also include the following components:water, fixed oils, polyethylene glycols, glycerol, petroleum, stearicacid, beeswax, other synthetic solvents or mixtures thereof;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as α-tocopherol acetate; chelating agents such asethylenediaminetetracetic acid; buffer such as acetates, citrates orphosphates; emulsifying agents such as polyoxyethylene monooleate andcoloring materials and adjuvants such as ferric oxide or talc. Thetopical preparation: can be enclosed in tubes, bottles, or jars made ofmetal, glass or plastic.

The invention is further illustrated by the following examples, givenfor illustrative purposes.

EXAMPLE 1

a. A mixture of 25.0 g of 3-bromomethyl-2-carbethoxythiophene, 18.2 g ofethyl 4-hydroxyphenylacetate, 55.2 g of potassium carbonate and 1.0 g ofsodium iodide in 500 ml of butanone is refluxed for 16 hours. The saltsare removed by filtration and washed with ether and the filtrateconcentrated in vacuo leaving an amber oil. The oil is dissolved inether and the ether solution washed with 5% sodium hydroxide and water,dried, filtered and the ether removed leaving a yellow oil. To asolution of the oil in 400 ml of ethanol is added 50 ml of water and80.0 g of potassium hydroxide and the reaction mixture refluxed for 16hours and then concentrated in vacuo. The aqueous solution is cooled andacidified with ice cold concentrated hydrochloric acid to provide asolid which is collected, dried and recrystallized from isopropanol andwashed to provide beige crystals, mp 222° C., of4-(2-carboxy-3-thienylmethoxy)phenylacetic acid.

b. To 3.5 ml of absolute ethanol is carefully added 5.80 g of phosphoruspentoxide while maintaining the temperature below 80° C. After totaladdition the white viscous mixture is heated at 110° C. for one hour and25 ml of tetramethylenesulfone is added. The reaction temperature isadjusted to 81° to 83° C. and 2.70 g of4-(2-carboxy-3-thienylmethoxy)phenylacetic acid introduced. Thetemperature of the reaction mixture is maintained for 3 hours and themixture is carefully poured into water, basified and extracted withtoluene. The aqueous phase is acidified with ice cold concentratedhydrochloric acid to provide a brown solid which is extracted withchloroform, filtered and concentrated in vacuo to a yellow solid. Thesolid upon trituration with ether provides light yellow crystals, mp162°-164° C., of 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-aceticacid.

Analysis: Calculated for C₁₄ H₁₀ SO₄ : 61.30%C; 3.68%H; 11.69%S. Found:61.47%C; 3.73%H; 11.58%S.

EXAMPLE 2

A mixture of 0.70 g of4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (Example 1),8 ml of concentrated sulfuric acid, and 150 ml of methanol is refluxedfor 16 hours. The reaction mixture is concentrated in vacuo, dilutedwith water and extracted with benzene. The combined benzene extracts arewashed with 5% sodium hydroxide and water, dried, filtered andconcentrated in vacuo to an oil which solidifies upon standing. Thesolid is recrystallized from methanol to provide light yellow crystals,mp 80°-81° C. of methyl4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate.

Analysis: Calculated for C₁₅ H₁₂ SO₄ : 62.48%C; 4.19%H; 11.12%S. Found:62.49%C; 4.28%H; 11.27%S.

EXAMPLE 3

A solution of 1.0 g of4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (Example 1),50 ml of isopropanol and 8 ml of concentrated sulfuric acid is refluxedfor 16 hours and then concentrated in vacuo leaving a dark brown oil.The oil is dissolved in chloroform, washed successively with water,saturated sodium bicarbonate solution and water, dried, filtered andconcentrated in vacuo leaving an amber oil which solidifies uponstanding. The solid is recrystallized from isopropanol to give colorlesscrystals, mp 92°-94° C., of isopropyl4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate.

Analysis: Calculated for C₁₇ H₁₆ SO₄ : 64.54%C; 5.10%H. Found: 64.42%C;5.17%H.

EXAMPLE 4

a. A mixture of 20.0 g of methyl 3-bromomethyl-2-furoate, 15.1 g ofmethyl 4-hydroxyphenyl acetate, 52.0 g of potassium carbonate and 1.0 gof sodium iodide in 360 ml butanone is treated according to themanipulative procedure described above in Example 1(a) to produce ayellow-brown precipitate which is recrystallized from acetonitrile togive off-white crystals, mp 204°-205° C., of4-(2-carboxy-3-furylmethoxy)phenylacetic acid.

b. To a mixture of 9.6 g of 4-(2-carboxy-3-furylmethoxy)phenyl aceticacid in 140 ml of anhydrous benzene is added 14.4 g of phosphoruspentachloride and the suspension stirred at ambient temperature for 4hours. The benzene is removed under reduced pressure at 85° C. toprovide the diacid halide as a light tan solid. This solid is dissolvedin anhydrous methylene chloride and 17.9 g of stannic chloride addedportionwise over a 5 minute period. The reaction mixture is stirred atambient temperature for 24 hours and then 140 ml of 1N hydrochloric acidis added and stirring continued for an additional 24 hours. The reactionmixture is basified, filtered, the organic layer separated, and theaqueous layer washed with ether and acidified to effect a brown solidwhich is filtered, washed with water, dried and then recrystallized fromacetonitrile to give a tan solid, mp 177°-178° C., of4,10-dihydro-10-oxofurano[3,2-c][1]benzoxepin-8-acetic acid.

Analysis:

Calculated for C₁₄ H₁₀ O₅ : 65.11%C; 3.90%H. Found: 65.29%C; 3.96%H.

EXAMPLE 5

a. A mixture of 3.6 g of ethyl 2-bromomethylnicotinate (50% product),2.7 g of ethyl 4-hydroxyphenylacetate, 8.3 g of potassium carbonate and0.2 g of sodium iodide in 60 ml of butanone is treated according to themanipulative procedure described above in Example 1(a) to produce abeige solid which is recrystallized from methanol and then washed with a1:10 mixture of acetonitrile and ether to give white crystals, mp185°-187° C., of 4-(3-carboxy-2-pyridylmethoxy)phenylacetic acid.

b. By following the manipulative procedure described above in Example1(b) a sample of 4-(3-carboxy-2-pyridylmethoxy)phenylacetic acid istreated to produce5,11-dihydro-11-oxopyrido[2,3-c][1]benzoxepin-9-acetic acid.

EXAMPLE 6

a. To a suspension of 10.9 g of ethyl4-formyl-1,2,5-trimethylpyrrole-3-carboxylate in 40 ml of methanol isadded dropwise under nitrogen 5.6 g of sodium borohydride in methanolwhile maintaining the reaction temperature below 50° C. after totaladdition the reaction mixture is stirred at ambient temperature for 4hours, then 90 ml of water introduced and the reaction mixture saturatedwith potassium carbonate and extracted with ether. The combined etherextracts are dried and concentrated in vacuo leaving a yellow solidwhich is recrystallized from cyclohexane to give ethyl4-(hydroxymethyl)-1,2,5-trimethylpyrrole-3-carboxylate, mp 184°-186° C.

b. 1.0 g of ethyl 4-(hydroxymethyl)-1,2,5-trimethylpyrrole-3-carboxylateis dissolved in 15 ml of benzene and 0.6 g of thionyl chloride is addeddropwise and after total addition the reaction mixture is stirred for3.5 hours at ambient temperature. The benzene is removed in vacuoleaving the gray solid, ethyl4-(chloromethyl)-1,2,5-trimethylpyrrole-3-carboxylate.

c. A mixture of 1.1 g of ethyl4-(chloromethyl)-1,2,5-trimethylpyrrole-3-carboxylate, 0.9 g of methyl4-hydroxyphenyl acetate and 0.29 gm of sodium methoxide in 30 ml ofmethanol is stirred at ice bath temperature for 5 hours and then atambient temperature for an additional 19 hours. The mixture is filtered,and the filtrate concentrated in vacuo leaving an oil. The oil isdissolved in ether and the ether solution washed with 5% sodiumhydroxide and water, dried, and the ether removed leaving a yellow oil.To a solution of the oil in 40 ml of ethanol is added 5 ml of water and8 g of potassium hydroxide and the reaction mixture refluxed for 16hours and then concentrated in vacuo. The aqueous solution is cooled,and acidified with ice cold concentrated hydrochloric acid to provide4-(4-carboxy-1,2,5-trimethyl-3-pyrrylmethoxy)phenylacetic acid.

d. By following the manipulative procedure outlined above in Example1(b) a sample of 4-(3-carboxy-1,2,5-trimethylpyrrylmethoxy)phenylaceticacid is converted to4,10-dihydro-1,2,3-trimethyl-10-oxopyrrolo[3,4-c][1]benzoxepin-8-aceticacid.

We claim:
 1. A process for the preparation of a compound of the formula##STR6## wherein X together with the carbon atoms to which it attachesis a thienyl radical R is hydrogen or straight or branched chain alkylof from 1 to 5 carbon atoms; R¹ is hydrogen or alkyl of 1 to 4 carbonatoms; R² is hydrogen or methyl; n is the integer 1, 2 or 3; and saltsprepared from pharmaceutically acceptable bases which comprisescyclizing, with a dehydrating agent at a temperature of from 50° to 125°C. and for a time of 5 minutes to 12 hours, a dicarboxylic acid of theformula ##STR7## wherein X and the carbon atoms to which it attaches,R¹, R² and n are as defined earlier.
 2. A process as defined in claim 1for preparing a 4,10-dihydro-10-oxothieno[3,2-c][1[benzoxepin-alkanoicacid which comprises cyclizing a dicarboxylic acid of the formula##STR8##
 3. A process as defined in claim 1 for preparing4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid whichcomprises cyclizing the dicarboxylic acid of the formula ##STR9##
 4. Theprocess as defined in claim 1 wherein the cyclizing is carried out inthe presence of a dehydrating agent selected from the group consistingof polyphosphoric acid, ethanol-phosphorus pentoxide and sulfuric acid.5. The process as defined in claim 1 wherein the cyclizing is carriedout with a solvent selected from the group consisting oftetramethylenesulfone and acetic acid.